These journal articles are reports are from various sources. When known, they are indicated. They are presented for educational purposes only, and not intended to diagnose or prescribe treatment for any medical condition.
Pemphigus vulgaris and Pemphigus Foliaceus
Bullous Diseases - Topics in Clinical Dermatology
The treatment of pemphigus vulgaris: experience with 48 patients seen over an 11-year period
Stephan Muller & John R. Stanley
Management of Blistering Diseases
Edited by Fenella Wojnarowska & Robert Briggaman 1990
Introduction
The term pemphigus stems from the Greek pemphix (blister) and describes a group of chronic blistering skin diseases in which autoantibodies are directed against the cell surface of keratinocytes, resulting in the loss of cohesion between epidermal cells, through a process called acantholysis. Pemphigus is divided into pemphigus vulgaris (PV) with a suprabasal acantholysis and pemphigus foliaceus (PF) with acantholysis in the upper parts of the epidermis. With these definitions in mind, we could classify pemphigus vegetans and pemphigus erythematosus, types of pemphigus with certain unique clinical features, as subtypes of PV and PF, respectively.
Clinical Features
Presentation
Pemphigus has a worldwide distribution with an annual incidence of approximately 0.1-0.5 per 100 000 population. The prevalence of PV in patients of Jewish origin is increased, and the annual incidence of pemphigus has been reported to be about 1.6-3.2 cases per 100 000 Jewish population. The disease has a peak incidence of occurrence in patients between the fourth and sixth decade.
Cutaneous distribution, mucous membrane involvement and morphology of lesions
PV is the most common type of pemphigus and comprises about 80% of patients with pemphigus. In more than 50% of cases the disease begins with oral lesions, which may precede the cutaneous lesions by several months or may be the major, if not only, manifestation in some patients. Even though 10-15% of patients present with cutaneous lesions only, the mucous membranes are ultimately involved in almost all cases. Mucous membrane lesions in PV usually are seen as painful erosions. Presumably because of trauma, intact bullae are rarely seen in the mouth. Lesions in the oral cavity are usually eroded, painful and heal slowly with peripheral extension through shedding of the epithelium. These lesions are of different sizes with irregular ill-defined borders. Most frequently buccal and palatine mucosa are involved. Extensive erosions and painful lesions in the mouth may result in decreased food intake which in turn may contribute to hypoproteinaemia and hypoalbuminaemia. Other mucous membranes may be involved and ulcerations of the vulva or the conjunctiva may result in an initial misinterpretation of the diagnosis. Lesions of pharynx, larynx, oesophagus, urethra, cervix and rectal mucosa have been reported.
In vivo studies
Using an in vivo model, Anhalt et al. also examined the role of circulating autoantibodies in the pathogenesis of PV. IgC fractions from patients with PV were passively transferred into neonatal Balb/c mice. These mice developed cutaneous blisters and erosions with histological, ultrastructural and immunofluorescence features of pemphigus. Control animals that were injected with normal human IgG did not develop similar changes. The pathological changes were dependent on dose and antibody titre; high-titre sera were most effective. The circulating antibody titre in the mice was correlated to the severity of the disease. Electron microscopy of lesions from these mice revealed a widening of the epidermal intercellular spaces between desmosomes in early lesions, and complete cell-cell detachment, even at desmosomes in older lesions. Using this same in vivo model, Roscoe et al. demonstrated that PflgG is also capable of causing acantholysis in the superficial epidermis of neonatal mice.
Mechanism of acanmolysis
Pemphigus antibodies may mediate acantholysis by triggering release of proteolytic enzymes from epidermal cells. Using the organ culture system discussed above, Schiltz and coworkers came to the conclusion that when pemphigus IgG autoantibody binds to the epidermal cell surface, cells respond by secreting a factor capable of causing acantholysis. Tbis factor, called pemphigus acantholysis factor (PAF), did not appear in control cultures incubated with normal IgG. PAF was capable of causing suprabasilar acantholysis in organ cultures, identical to that seen with PV serum. PAF was thought to be a proteolytic enzyme, active near neutral pH. These studies suggested that the binding of the pemphigus antibody to the epidermal cell surface resulted in activation, release or synthesis of a non-lysosomal proteolytic enzyme that was involved in the loss of cell adhesion.
There are some recent data to suggest that the PAF proteolytic enzyme is a plasminogen activator. In-non-keratinocyte cell systems, Becker, et al reported that production of plasminogen activator, a serine proteinase that catalyses the conversion of plasminogen to plasmin, could be activated by incubating cells with antibodies. In addition, the purified anti-cell surface IgG produced a rapid change in morphology of these cells with 2 h. Cells became rounded and detached from the culture dish surface. Keratinocytes incubated with pemphigus anti-cell surface antibodies show a similar effect. Singer et al. incubated confluent primary cultures of neonatal human epidermal cells with affinity-purified plasminogen free IgG from patients with pemphigus. After 24 h a tenfold increase in extracellular plasminogen activator and a fivefold increase in cell-associated plasminogen activator was found with PF IgG. After incubation with PV IgG, the increase in extracellular plasminogen activator was sevenfold and the increase in cell-associated plasminogen activator sixfold. Biochemically and immunologically, two types of human plasminogen activator can be identified: a urokinase qpe with a molecular weight of 52 000-55 000 and a tissue type with a molecular weight between 60 000 and 74 000. By SDS-PAGE (SDS polyacrylamidegel electrophoresis) it was shown that the plasminogen activator activity secreted by cultured human epidermal cells had a molecular weight of 55 000, suggesting it to be a urokinase-type enzyme. The importance of plasminogen activator and plasmin in causing acantholysis was studied in organ cultures. Addition of plasmin inhibitors such as aprotinin and lima bean trypsin inhibitor prevented the development of acantholysis when either PV or PF IgG were added to skin in organ cultures. In addition, both plasminogen and PF IgG were required to cause acantholysis.
The stimulation of plasminogen activator could be inhibited by corticosteroids. Dexamethasone at a concentration 0f 10-10M inhibited extracellular plasminogen activator activiq by 60% after incubation of epidermal cells with PF IgG. At 10-8M, dexamethasone inhibition reached 95%. These findings may account for the beneficial effects of corticosteroids on the course of pemphigus.
In summary, these findings indicate that the first step in the pathogenesis of pemphigus is the binding of autoantihody to the surface of human epidermal cells, which may stimulate the production of a plasminogen activator of the urokinase type. Plasminogen would then be converted to plasmin which may be responsible for the loss of cellular adhesion. This pathophysiological scheme is tentative and other proteins, such as complement, and or other mechanisms, including direct effects of IgG on cell adhesion, may also prove to be important.
Treatment
Currently the first-choice therapy for both types of pemphigus is corticosteroids, usually in the form of oral prednisone. Tbe goal of therapy is to control the disease at the lowest possible dose of prednisone. If tbe disease is severe then daily prednisone at a bigh dose (60 mg a day or greater) is given to get the disease under control. If the initial disease activity is mild or limited, then lower doses can be tried. Once the disease is under control, the prednisone dose is tapered, if possible, to an alternate-day regimen. The object is to control the disease at the lowest possible alternate-day dose of prednisone. PF is often mild enough to require only topical corticosteroids for control.
If the disease cannot be controlled on a low alternate-day dose of prednisone, then adjuvant therapy is often used to try to lower the dose of prednisone needed. The most effective adjuvant therapy is not known. However, there are three main drugs used - gold, azathioprine and cyclophosphamide.
The mechanisms responsible for the effects of gold treatment in pemphigus are not known. It is speculated that gold compounds act in vivo by altering the pathways of inflammatory response, such as mediator generation and/or the activation of degradative enzymes. Gold might also alter phagocytic cell function, or T Iymphocyte function. Dermatological side effects of gold therapy are manifold. In a series of patients studied by Penneys non-specific eczematous reactions are described. Lichen planus-like eruptions, pityriasis rosea-like eruptions generalized erythroderma and gold cheilitis and stomatitis were observed as well.
An acute vasomotor reaction, which may lead to myocardial infarction, has been reported with intramuscular gold, especially the thiomalate preparation. Further complications of gold therapy include anaphylaxis, proteinuria, nephrotoxicity, leucopenia and thrombocytopenia, aplastic anaemia, intrahepatic cholestasis, pulmonary fibrosis and deposition of gold compounds in the cornea and lens leading to chrysiasis. An intramuscular preparation such as aurothioglucose or gold sodium thiomalate is usually administered for pemphigus. Experience with oral gold therapy and pemphigus is limited.
In summary, gold therapy may have a corticosteroid-sparing effect and some patients can be controlled on gold medication alone. However, gold, like corticosteroids, have serious side effects.
The most commonly used adjuvant therapy in pemphigus is the administration of cyclophosphamide or azathioprine. Usually one of these drugs is given together with corticosteroids, but after a latent period of between 4 and 8 weeks it may be sufficient, especially in mild forms of pemphigus, to control disease activity. In patients with more active disease, these immunosuppressive drugs may provide a corticosteroid-sparing effect. Since no controlled studies are available on the efficacy of these drugs and since spontaneous remissions may occur even in untreated pemphigus, especially in PF, the evaluation of case reports is difficult.
The belief that immunosuppressive drugs do, indeed, have a corticosteroid-sparing effect is based on individual observations. Serious side effects of these drugs include toxic effects on bone marrow and liver. Cyclophosphamide can also induce sterility in men and women as well as hemorrhagic cystitis. The long-term administration of immunosuppressives may be associated with higher risk of developing malignant neoplasia.
In severe uncontrollable pemphigus other therapeutic approaches have also been tried. Plasmaphaeresis is a procedure that decreases the level of circulating antibodies, including pemphigus anti-epithelial cell surface antibodies. Since the antibody level rebounds due to the feedback regulation of antibody synthesis it is necessary to combine this therapy with immunosuppressive drugs such as cyclophosphamide. Following repeated plasmaphaeresis, a gradual decline in antibody levels associated with a concurrent improvement in clinical symptoms has been reported.
Another alternative is the so-called corticosteroid pulse therapy. High doses of methylprednisolone are administered once a day for 5 days. Patients must be in electrolyte balance prior to the initiation of pulse therapy and carefully monitored during therapy. Sudden death resulting from electrolyte shifts may occur.
Finally, in a recent report nine patients with PF were treated with dapsone. The authors reported improvement in the five patients who had low or negative levels of circulating anti-epithelial cell surface antibodies.
Prognosis and Therapy
In the pre-corticosteroid era PV was usually a fatal disease. Most patients died within 5 years of the onset of the disease. On the other hand prognosis was better in patients with PF. Except for occasional acute cases with generalized involvement, PF follows, in the majority of patients, a very chronic course, that may extend over many years with rare acute exacerbations. One reason for the difference in prognosis between PV and PF is probably the difference in the level of the epidermis at which blister formation occurs. In PF only the very superficial epidermis is lost, whereas in PV the entire epidermis, with the exception of the basal layer, is gone.
The advent of corticosteroid therapy dramatically improved the prognosis of pemphigus. Subsequent to the widespread use of corticosteroids, the mortality rate has drastically dropped from 73% reported between 1941 and 1950 to less than 30% soon after the introduction of corticosteroids and, recently, is down to probably less than 10%.
With current therapy most of the fatal outcomes are due to infections, secondary to a combination of difficult-to-control disease with persistent skin erosions and immuno suppression from therapy
Bullous Diseases - Topics in Clinical Dermatology
Edited by Jo David Fine, MD
In paraneoplastic pemphigus, the humoral immune response is more complex and less well defined. Current data indicate that these sera immunoprecipitate a complex of epithelial antigens consisting of desmoplakin I and desmoplakin II (intracellular plaque proteins common to desmosomes of all epithelia) and 230-kD bullous pemphigoid antigen (a plaque protein of hemidesmosomes, and at least two other antigens that have not yet been characterized. The autoantibodics of paraneoplastic pemphigus are most distinctive because they bind to the cell surface of all epithelia, not just to stratified squamous epithelia. The implications of autoantibodies with such a broad specificity is not yet clear, and passive transfer of these autoantibodies into mice reproduces lesions only in skin and esophagus.
However, a recent report showed that a patient with paraneoplastic pemphigus suffered from dyspnea and hypoxia, and bronchoscopy revealed laryngeal, tracheal, and bronchial erosions with histologic signs of cell dysadhesion. Direct immunofluorescence performed on bronchial epithelium showed deposition of autoantibodies on the respiratory epithelium, suggesting that the pemphigus autoantibodies were the cause of the respiratory tract erosions. The multiorgan effects of these unique autoantibodies are being studied in additional cases, and it appears that this is a more devastating illness, with autoantibody-induced damage to numerous tissues that express desmoplakins. The potential targets include respiratory and gut epithelium, skin and mucosal epithelium, and myocardium and bladder epithelium.
Immunogenetics
Pemphigus Vulgaris
It has long been suspected that a genetic predisposition exists in pemphigus vulgaris, based primarily on the observation that this disease appears to occur more frequently than normal in Askenazi Jews. HLA serologic studies demonstrated a strong association between the presence of HLA-DR4 and HLA-DR6 haplotypes and pemphigus vulgaris.
One recent study of both Israeli and non-lsraeli HLA-DR4-positive pemphigus vulgaris patients demonstrated a significant enrichment of the DR1 variant (Dw10) in these patients (detected by the mixed lymphocyte reaction). Twentyfour of 24 Israeli patients and 10 of 14 non-Israeli patients were Dw10 positive. The polypeptide product of this HLA-DR4 Dw10 haplotype differs from those of other HLA-DR4 haplotypes by only three amino acids (ILE-67, ASP-70. GLU-71 in the third hypervanable region of the DR1 chain.
Serologic studies have also been performed on HLA-DR6-positive pemphigus vulgaris patients. One recent study evaluating Israeli Askenazi Jews, Israel non- Askenazi Jews, and a non-Jewish Austrian pemphigus population demonstrated that Israeli pemphigus patients were HLA-DR6 and DQwl positive, possessing a rare DQ allele designated DQ1.3. DQ1.3 differs from the normal DQ1 haplotypes only by a valine to aspartic acid substitution at codon 57 of the DQ1 beta chain. This allele was seen only in Israeli pemphigus vulgaris patients (100%) and was completely absent in the Austrian pemphigus control patients.
These data suggest that alterations in the hypervariable region of thc 1 chain of HLA class II genes may confer susceptibility to pemphigus vulgaris. Even with the inherited immunogenetic predisposition, there must be a second hit that induces autoantibody production. The nature of this second event is completely unknown in pemphigus vulgaris. In some forms of pemphigus foliaceus, there are strong clues to the potential environmental events that may initiate autoimmunity.
Pemphigus Foliaceus
In contrast to pemphigus vulgaris, which is an autoimmune disease producing acantholysis in the suprabasal cell region in the epidermis, pemphigus foliaceus and its Brazilian variant, fogo selvagem, produce acantholysis high in the epidermis, through the granular cell layer, just below the stratum corneum. Intact flaccid blister formation is unusual, but widespread scaling and superficial denuding of skin are common. Unlike pemphigus vulgaris, which in the pre-corticosteroid era was universally a lethal disease, pemphigus foliaceus is a chronic, debilitating disease, that infrequently results in death.
At present, little is known about the immunogenetics of pemphigus foliaceus, but recent studies in Brazil of fogo selvagem suggest an immunogenetic component. Fogo selvagem family studies have demonstrated the frequent occurrence of disease in more than one family member. For example, in one series of 604 patients, 161 cases of fogo selvagem involved more than one family member. In 443 families, there was a single case of fogo selvagem; in 59 families, there were two cases in each family; in 7 families, three cases in each; in 3 families, four cases in each; and in 2 families, there were five cases of fogo selvagem in each family. In the majority of the 161 cases, fogo selvagem occurred in genetically related members of the family (i.e., parent and child or siblings, as opposed to husband and wife).
Another study has reported the occurrence of 485 cases of fogo selvagem in 201 families. This amounted to 18% of the 2,663 patients reported in this series. The disease affected a brother and a sister in 30 families: a mother and a son in 18: sisters in 17: and brothers in 16 families. In 187 of the 201 families (93%), fogo selvagem occurred in genetically related members, whereas in only 14 families (6.9%) it occurred in genetically unrelated members.
Two additional smaller studies have also reported the occurrence of fogo selvagem in one or more genetically related family members. One study reported 24 cases out of 506 occurring in 11 families. Another study reported 55 cases occurring in a series of 464 fogo selvagem patients in families in which more than one member was affected.
Preliminary HLA studies in fogo selvagem have been recently reported. A study of 48 Brazilian patients demonstrated increased frequencies of HLA-DR1, DQ1, and DR4. Decreased frequencies of HLA-DR3, DQ2, and DR7 were noted. HLA-DR1 was found in 14 of 24 (58.3%) fogo selvagem patients and in only 39 of 192 controls (20.3%; p = 0.00001). The relative risk was 5.5. HLA-DR4 was found in 10 of 24 patients (41.6%) and in only 32 of 192 controls (16.6%; p = 0.005). The relative risk was 3.6.
Therapy
Pemphigus Vulgaris
Corticosteroids are the drugs of choice in all patients with pemphigus vulgaris Topical therapy alone will never control the disease for long, for as outlined in detail, this is a systemic autoimmune disease, and as long as there are adequate amounts of autoantibody binding in the skin, lesions will be induced. The primary target for therapeutic intervention is the immunoglobulin-producing hematopoietic system, not the affected end organ, the skin.
Previously it was routine to use a regimen with an initial dosage of prednisone of 80 mg/day. If satisfactory control of the disease was not observed in about 1 week, the dosage was doubled to 160 mg/day. If necessary, after another week the dosage was doubled again With this regimen, patients often were exposed to dosages of prednisone in the range of 200-400 mg/day. The potential for life-threatening complications such as sepsis increases dramatically whenever the dose exceeds 2 mg/kg/day. Consequently, this regimen is far less popular than in the past.
Most patients can be controlled with prednisone, 1.0-2.0 mg/kg/day in divided doses. Subsequently, this may be consolidated into a single daily dose and then tapered. The tapering may be relatively rapid at first (5-10 mg/week). but it should proceed more slowly as the dosage reaches 40 mg/day. Once this dosage is achieved, an alternate-day regimen should be started. This can be done by tapering the dosage administered on every other day until the values are 40 mg and 0 mg on alternate days. The alternate-day high dosage can then be tapered.
The disease is apt to develop flares of activity during this period, and treatment of such relapses must be individualized. Some patients can be maintained for decades on low doses of prednisone, and alternate-day therapy reduces the well-known side effects of steroids dramatically.
One must be careful about the possible variability of generic preparations of prednisone. If a patient is not demonstrating a uniform response to oral prednisone therapy, it may be advisable to prescribe Deltasone rather than generic prednisone to eliminate variations in bioavailability of the drug. Prednisone is the corticosteroid used most frequently in the United States for pemphigus, but in other countries oral triamcinolone is used because (anecdotally) it is asserted that there are fewer long-term complications with this particular formulation.
Corticosteroid pulse therapy has also been used in certain patients. In this regiment, 1 g of methylprednisolone is given daily in an intravenous infusion lasting for 3 hours on 5 consecutive days. This is reported to provide rapid healing of lesions. There is a potential risk of sepsis, sudden death due to arrhythmia in elderly or debilitated patients, and possible aseptic necrosis of the femoral heads. Most patients can be controlled with lower doses of corticosteroids used in combination with immunosuppressive drugs.
Immunosuppressive drugs in addition to prednisone are required in about half of the cases of pemphigus vulgaris. Immunosuppressive drugs used in the treatment of pemphigus include cyclophosphamide (Cytoxan), azathioprine (Imuran),. methotrexate, and cyclosporin. These drugs are listed here in the order of their effectiveness (in my own experience). Immunosuppressive drugs are usually started when the prednisone tapering has begun. During initial therapy with large doses of prednisone, the addition of these drugs may produce profound immunosuppression with hazardous consequences.
Cytoxan appears to be the-most efficacious immunosuppressive drug, for it is more effective in reducing Ig synthesis than is azathioprine or methotrexate. This is because radiomimetic alkylating agents such as Cytoxan and chlorambucil have a preferential effect on B cells that Imuran does not. Although Cytoxan is much more effective, it is a very toxic drug, but the side effects are reasonably predictable Cytoxan is given in a single dose of 1-2 mg/kg/day. The major side effects are bone marrow suppression, hemorrhagic cystitis, bladder fibrosis, sterility, and an increased risk of malignant disease. Marrow suppression is expected with the use of Cytoxan, and frequently no clinical effect is observed until the leukocyte count has deceased. It is important to remember, however, that the effect on the white cell count is masked by high doses of prednisone; that elderly patients are more sensitive to the drug than younger patients; and that the drug appears to kill hematopoietic stem cells, so that the longer a patient is treated with the drug, the lower the dose that is required. The risk of hemorrhagic cystitis and bladder fibrosis can be reduced by insisting on an oral fluid intake of 2 liters/day. The most serious potential side effect involve malignant change. The risk that such treatment will result in the emergence of a bladder carcinoma or another malignant tumor is not known exactly, but patients who have been treated with Cytoxan for Wegener's granulomatosis have shown a significant increase in lifetime risk for the development of hematopoietic malignancies, leukemia, and bladder carcinoma. This risk appears to approach a 5-10% lifetime incidence. The possibility of this side effect makes one reluctant to use this drug in a young patient. Azathioprine, of course, has a similar potential for allowing lymphoid malignancies to emerge, but the lifetime risk is lower. apparently in the 2-3% range.
In addition, cyclophosphamide is myelosuppressive, and if a patient is not monitored very closely (weekly initially), unexpected and sometimes profound neutropenia can result. This particular side effect is rare with Imuran. Fortunately, Cytoxan works much more quickly than Imuran (therapeutic effects start after 7-10 days of initiation of therapy), and if neutropenia occurs, it can be reversed within 7-10 days after discontinuation of the drug. Imuran, on the other hand requires 6-8 weeks to have a therapeutic effect, and serious side effects are reversed more slowly.
Azathioprine, the major alternative immunosuppressive drug, is preferred by some physicians because it is easier to use, has a lower incidence of serious side effects, and does not require such close monitoring. It is administered in a dosage of 1-3 mg/kg/day and can be used if cyclophosphamide does not produce satisfactory results, if urinary tract complications develop, or if the patient cannot be monitored on a weekly basis. A problem peculiar to Imuran is the development of hepatotoxicity with fever. This occurs usually after 1 or 2 weeks of therapy. The patient will have signs or symptoms closely mimicking those of sepsis, but liver function tests will be elevated. This is an uncommon but very characteristic side effect of Imuran.
Methotrexate initially was used more extensively because most dermatologists were more familiar with this drug than with either Cytoxan or Imuran. However it is not as effective as these other drugs.
Intramuscular administration of gold sodium thiomalate has also been used for both pemphigus vulgaris and pemphigus foliaceus. The mechanisms by which it works are unknown. The treatment regimen is similar to that for rheumatoid arthritis. A test dose of 5 or 10 mg is given, followed by 25 mg 1 week later. After that, 50 mg is given at 1 to 4-week intervals; a therapeutic effect usually is expected after a total dosage of 500 mg has been administered. A complete blood count, urinalysis, and examination of the urine sediment must be done prior to each injection.
The possible side effects include a persistent and troublesome lichenoid demtatitis. acute nephritis, thrombocytopenia, and neutropenia. Nephritis usually is detected early only by an abnormal urinary sediment, often by the appearance of microscopic hematuria. Proteinuria and the nephritic syndrome may progress even if the drug is discontinued, and rarely glomerulonephritis may occur. The probability of side effects requiring discontinuation of the drug is about one in four.
Reports in the literature indicate that chrysotherapy is of benefit in some patients, but the exact value of this treatment is unclear. I have not been convinced that it is efficacious in pemphigus vulgaris, and two of my patients have developed sudden and significant complications. One patient developed allergic pneumonitis, requiring admission to an intensive care unit for a prolonged period; a second patient developed acute nephritis and proteinuria in excess of 4 g/day that persisted for 6 months.
I have not yet had any experience with oral gold therapy. but considering the unimpressive therapeutic effect of intramuscular gold therapy. I doubt that it will be more helpful.
It has been stated that intralesional injections of Kenalog (10 mg/ml) promote healing of localized lesions, especially oral lesions that may persist despite overall improvement. I have found them to be of little benefit. Topical steroid treatment can provide limited benefit in pemphigus vulgaris. Twice daily applications of Lidex gel can help reduce the crusting of scalp lesions and benefit oral lesions to a limited extent.
The role of plasmaphaeresis in the treatment of pemphigus has been debated, primarily because there are few controlled studies of this uncommon disease. It is almost never indicated in pemphigus foliaceus but can be used in severe cases of pemphigus vulgaris. It has been used in a few patients with paraneoplastic pemphigus, but with unclear results.
In pemphigus vulgaris it has been shown that the autoantibody, although abnormal, is still under feedback inhibition by the immune system. If one only performs plasmaphaeresis and removes the pathogenic antibody, one can actually stimulate the antibody-producing B cells and observe a rebound flare weeks or months after the plasmaphaeresis is discontinued. Therefore, it is imperative that plasmaphaeresis be used in conjugation with immunosuppressive therapy to prevent this rebound effect.
The most effective way of using plasmaphaeresis is to treat patients with severe pemphigus vulgaris with the following regimen:
The patient is placed on prednisone, 1 mg/kg/day
Cytoxan, 2 mg/kg/day
Receives a 2-week course of intensive short term plasmaphaeresis
This involves a total of five high-volume plasma removals ( 3 to 4 liters per pheresis) over a period of 2 weeks. Cytoxan and prednisone are started at the beginning of the 2-week pheresis session. At the end of the session, there will be some early clinical improvement due to removal of the autoantibody. At this time, it is important to start a slow taper of the prednisone but to maintain Cytoxan on board. This takes advantage of the fact that the pheresis actually stimulates the antibody producing B cells, which are then selectively killed by the Cytoxan. The proliferating B cells are extremely sensitive to alkylating agents such as Cytoxan and chlorambucil. Imuran or other immunosuppressive drugs are not as effective as alkylating agents in this method.
There are several caveats in the use of plasmaphaeresis. In a poorly controlled study, it has been shown that if patients are maximally suppressed with prednisone and immunosuppressive agents and receive pheresis, they are at higher risk of sudden death from sepsis. In addition, the treatment is very expensive. The first plasma exchange costs approximately $l,000. each subsequent exchange costs approximately $600 to $700, and in addition, a 2-week hospitalization period is necessary to administer the therapy. Therefore, because of the risk of sudden death from sepsis and the high cost, plasmaphaeresis is indicated only in the most refractory cases where the patient is clearly at risk of dying from the disease itself.
To summarize the therapies succinctly, patients with pemphigus vulgaris should first be treated with oral corticosteroids: approximately half of these patients will be controlled without unnecessarily high doses of these drugs. Refractory patients can be treated with azathioprine if they cannot be closely monitored, or are unreliable in any way, or are concerned about the possible carcinogenic effect of other agents. Cytoxan plus plasmaphaeresis should be reserved for the most severely affected patients and for those who can be monitored closely over both the short and the long term.
Pemphigus Foliaceus
By light microscopy, pemphigus foliaceus differs from pemphigus vulgaris in that the intraepidermal blister formation is very superficial. occurring just below the stratum corneum. Clinically. it can also be differentiated. Oral lesions are rarerly observed, and hyperkeratotic and crusted lesions are prominent. Fogo selvagem is an epidemic form of pemphigus foliaceus that occurs mainly in central Brazil.
In general, the options available for the treatment of pemphigus foliaceus are similar to those for pemphigus vulgaris, but far less aggressive drug therapy is used because the disease has a better prognosis than pemphigus vulgaris. Most patients can be controlled with a combination of very low oral doses of corticosteroids and potent topical steroid therapy. The use of immunosuppressive drugs is almost never required, but in the rare severe case that requires a second drug, the choice of drugs and their usefulness are similar to those for pemphigus vulgaris.
Drug Induced Pemphigus
Pemphigus has been reported to occur during treatment with several different drugs. Most commonly. a clinical disease resembling pemphigus foliaceus occurs during treatment with d-penicillamine and captopril. Pemphigus vulgaris is also associated with the use of these drugs, but this is less common than pemphigus foliaceus. It is important to recognize that not all patients with drug-induced pemphigus have demonstrable evidence of autoantibody production.
The skin biopsy specimen shows acantholysis, but direct immunofluorescence shows only complement components in the epidermal intercellular spaces, and indirect immunofluorescence examination for circulating antibodies is negative. In these cases, it is likely that the acantholysis is due to a direct action of the drug on the epidermis.
In support of this theory, it has been shown that penicillamine and captopril can produce acantholysis in organ cultures of skin without the addition of human antibodies. In these cases in which autoantibody production is not demonstrable the disease resolves over a period of 6 to 8 weeks after withdrawal of the drug. It is not necessary to treat these patients with systemic steroid therapy or other drugs although topical application of a potent steroid such as Topicon (desoximetasone 0.25%) helps reduce crusting and discomfort in the lesions.
However, in the majority of cases in which patients treated with these drugs develop pemphigus, they do develop autoantibodies, which are present both in the perilesional epidermis and circulating in the serum. The relationship of drug treatment to the development of true autoimmunity in these patients is a challenging question for investigators. These patients appear to have true pemphigus and must be treated as if they have idiopathic pemphigus foliaceus (or vulgaris).
Paraneoplastic Pemphigus
In paraneoplastic pemphigus, no consistently effective therapy has yet been devised. In general. all patients who have had a benign neoplasm associated with the syndrome and whose neoplasm has been removed have recovered completely from their disease. With perhaps one or two exceptions, all patients who have had a malignant neoplasm associated with paraneoplastic pemphigus have died despite therapy with all of the above-stated therapies, as well as cyclosporin. dapsone, and other agents. At present. paraneoplastic pemphigus developing in the context of a malignant neoplasm is almost universally fatal.
by Thomas T. Provost & William L. Weston , 1993
Treatment
Pemphigus Vulgaris
Corticosteroids are the drugs of first choice for treatment of pemphigus vulgaris but may need to be combined with an immunosuppressive agent to reduce their side effects. Most patients respond to prednisone 1 to 2 mg per kg daily in divided doses. Initially controlling the disease with higher doses of prednisone (200 to 400 mg per day) has been advocated, but this can increase the risk of life-threatening infection Response to therapy should be evaluated by assessing healing of existing erosions and reduction of new blister formation. Once the disease is under control, prednisone can be consolidated into a single morning dose and then tapered rather rapidly at first but more slowly when nearing a dose of 40 mg per day. If the disease remains under control at 40 mg daily, then an attempt to go to alternate day therapy should be made by gradually tapering the dose given every other day to zero. The 40 mg every other day should then be tapered as tolerated.
If high maintenance doses are required or if the patient is not tolerating prednisone, then addition of an immunosuppressive agent should be considered to help allow steroids to be used at a lower dose or eliminated altogether. Immunosuppressive agents which have proven beneficial are cyclophosphamide (Cytoxan), azathioprine (Imuran), and methotrexate. These agents take several weeks to take effect and are not drugs of first choice for treating the acute phase of pemphigus vulgaris. They are usually not started until the prednisone has been tapered to about 40 mg daily. When the disease is controlled by prednisone and the immunosuppressive agent, attempts should be made to decrease the prednisone by 5 to 10 mg weekly. If the prednisone can be discontinued, the immunosuppressive agent should be tapered over several months as tolerated.
Cytoxan is used in doses of 1 to 2 mg per kg daily. Significant adverse effects include bone marrow suppression, hemorrhagic cystitis and bladder fibrosis, sterility and increased long-term risk for development of malignancies. These side effects mandate routine monitoring of CBC and routine and microscopic urinalysis. The risk of Cytoxan can be reduced by encouraging patients to maintain a high fluid intake.
Imuran is also given in doses of 1 to 2 mg per kg daily and can be useful in patients with urinary tract problems or those not responding to Cytoxan. It shares with Cytoxan the side effects of bone marrow suppression and increased risk of developing malignancies but also has been associated with hepatotoxicity. Therefore chemistry profile and CBC should be followed routinely.
Less often, methotrexate has been used as adjunctive therapy; 25 to 30 mg are given weekly, either intramuscularly in one dose or orally divided into three doses, given 12 hours apart. Because of hepatotoxicity, routine chemistry screens are necessary, and liver biopsies, both pretreatment and during therapy, are suggested if long-term treatment is anticipated.
Intramuscular gold sodium thiomalate (Myochrysine) and gold thioglucose (Solganal) have both been used successfully as steroid sparing agents. A test dose of 10 mg is given, followed by a 25 mg dose 1 week later. If the drug is well tolerated, therapy is started, usually with 50 mg weekly. The response is slow, with beneficial effects usually noted after a total dose of 500 mg. When acceptable control is achieved maintenance therapy may then be instituted. Approximately 40% of patients on gold experience adverse effects. The majority of these are not serious, but life-threatening complications can occur. Side effects include nitroid reactions, mucocutaneous eruptions, nephritis, leukopenia, and thrombocytopenia. A CBC and urinalysis including microscopic examination must be done before each injection.
Plasmaphaeresis has been of short-term benefit in controlling pemphigus vulgaris, but its use should be restricted to extraordinary circumstances.
Topical care for the crusted and weeping lesions should include wet Domeboro compresses three to four times daily, to help remove crusts and decrease discomfort and silver sulfadiazine cream (Silvadene cream), to reduce the risk of infection. In the acute phase, frequent cultures and appropriate antibiotics are important to minimize infection.
Patients with oral involvement may benefit from a soft diet and viscous lidocaine before meals; topical triamcinolone acetonide in an adherent base (Kenalog in orabase) may be of some help.
In the pre steroid era, pemphigus vulgaris had a substantial mortality (50% mortality within 12 months of disease onset). Presently, the mortality rate in treated patients is about 10%, largely related to steroid and immunosuppressive therapy complications. Although the course of pemphigus vulgaris is often chronic, treatment can result in long-term remission of the disease.
Endemic Pemphigus Foliaceus (Fogo Selvagem)
The cutaneous eruption of the great majority of patients with fogo selvagem responds to treatment with systemic corticosteroids alone. In a few patients however, despite the use of steroids, the disease runs a chronic course and all the side effects of the therapy, i.e. Cushing's syndrome, osteoporosis, and so on, are found. These mucosal lesions do not usually occur in this disease, it is surprising that the majority of patients have in vivo bound pemphigus autoantibodies in the ICS of the oral and esophageal mucosa. The explanation of this interesting observation remains elusive. It is conceivable that fogo selvagem autoantibodies detected by IF techniques may have idiotypic specificities. Certain epidermal epitopes may be bound by the respective autoantibodies and trigger acantholysis, whereas other epitopes located in epithelial tissues other than the epidermis may be pathogenetically irrelevant.
To study the restriction of the autoantibody response in patients with fogo selvagem, a study was conducted on the sera of patients (n = 196), their relatives (n = 138), their cohabitants (n = 13), and normal donors from endemic (n = 38) and nonendemic areas (n = 44) by indirect IF. Additionally, ANA and anti-nDNA antibodies were also determined by indirect IF against Hep-2 cells and Crithidia lucilliae, respectively, and autoantibodies against nRNP, Ro/SSA, La/SSB, and Sm were assayed by double-immune diffusion in agarose gels. Fogo selvagem autoantibodies were present in the sera of all patients with active disease (n = 196, 100%, titers 40 to 2560) but were not found in any sera of normal individuals from endemic or non endemic areas. The titer of the fogo selvagem autoantibodies showed a rough correlation with the extent and activity of the disease. Furthermore, lupus-associated autoantibodies were not present in any of the tested samples. This study concluded that fogo selvagem autoantibodies are specific serological markers of the disease and are not present in unaffected individuals. Therefore they provide an important marker that should be useful in ongoing epidemiological studies aimed at identifying putative etiological agent(s) of fogo selvagem.
Immunopathogenesis of Pemphigus Vulgaris and Endemic Pemphigus Foliaceus
Autoimmune response in pemphigus
As a proved autoimmune disease involving a single and highly accessible organ, pemphigus is an ideal model for studying factors underlying autoimmunity. It is now well established that pemphigus autoantibodies are directly involved in pathogenesis. Furthermore, these autoantibodies are directed against self-antigens that are present in normal squamous epithelium. Although the precise cause for self-tolerance breakdown is unknown, alterations in normal immunoregulatory mechanisms are likely to be involved.
Some evidence also suggests that genetic factors may play a role in the development of pemphigus. For example, pemphigus vulgaris occurs in all ethnic and racial groups, but the incidence is higher in Jewish people: HLA-A26, HLA-B38, SC21, and HLA-DR4 were found in Ashkenazi Jews and HLA-DR4 and HLA-DRw6 were found in non=Ashkenazi Jews having pemphigus vulgaris. These markers were absent in less than 5% of patients. Szafer et al reported that in pemphigus vulgaris there were disease-specific RFLPs as detected by DQ beta probe: DQwl (2.5kb Bam HI) and DQw3 (6.9 kb Pvu II). Recently, Ahmed et al found that 92% (n = 26) of pemphigus vulgaris patients (Ashkenazi Jews) expressed the HLA-DR4 and HLA-DQw3 (all were DR4, DQw8 [DQ"3.2"]). From these, 75% express extended haplotypes: HLA-B38, SC21, DR4 and HLA-B35, SC31, DR4. A potential susceptibility gene mapped to DR4, DQw8 region. This pemphigus vulgaris gene was inherited as a dominant trait.
Fewer definitive genetic studies have been carried out on pemphigus foliaceus. In Japan, HLA-typing studies have also shown a statistically significant incidence of HLA-DR4, with a higher frequency in pemphigus foliaceus than pemphigus vulgaris. In fogo selvagem, epidemiological studies have shown an 18% increase incidence of disease among family members, 93% of whom are genetically (i.e., consanguineously) related. These findings strongly suggest that genetic factors may be important.
Recent studies in fogo selvagem show a strong association of the disease with Class II HLA alleles. Petzl-Erler and Santamaria showed that 37 out of 42 patients (88%) with fogo selvagem had one or both of the HLA-DR1 and DR4 genes, whereas these genes were present in only 34% of the controls (n = 64). Furthermore, the DR7 marker was found in only one ot the 42 patients testcd and in 29% of thc controls. Using serological and DNA-typing analysis, Moraes ct al have extended the earlicr HLA studies of Petzl-Erler. They found the HLA-DR1-Dw20 (DRB1*0102) gene (confers susceptibility) in 15 of 37 patients and in only 4 of 47 controls (relative risk of 7.3) and an absence of HLA-DQw2 allele (DQB1*0201) (confers resistance) that was detected in 11 of 49 controls. Healthy family members carried the dominant allele HLA-DQw2, which prevents the development of the disease in exposed individuals. HLA studies in two families of fogo selvagem patients support these conclusions (i.e., patients were DRI-Dw20 positive and DQw2 negative, and healthy relatives were HLA-DQw2 positive with DR1-Dw20 positive or negative).
Therefore it is conceivable that a susceptible individual who is exposed to the appropriate environmental antigen may produce antibodies that, in turn, cross react with a kerainocyte surface epitope (antigenic mimicry), causing acantholysis and the clinical expression of the human disease known as fogo selvagem.
Relatively little is known about other factors that influence the expression of autoimmunity in pemphigus. No significant gender predisposition is apparent. Although associated with other autoimmune disorders, in particular myasthenia gravis and benign thymomas, the course of pemphigus is usually not affected by these disorders. Pemphigus has also been associated with various malignancies, including lymphoreticular neoplasms.
A new syndrome, paraneoplastic pemphigus, has been recently described by Anhalt et al in a group of patients with a vesiculoerosive process of skin and mucosas in which autoantibodies work against desmosomal and hemidesmosomal proteins. The autoantibodies were pathogenic by passive transfer experiments, and their antigens were identified as desmoplakin I and II, the 230 kD bullous pemphigoid, and a 190 kD epidermal protein.
Several studies of cell-mediated immunity suggest the presence of an underlying defect in immunoregulation. It was demonstrated that peripheral blood lymphocytes from pemphigus vulgaris patients stimulated in vitro with phytohemagglutinin have delayed IL-2 production and decreased IL-2 receptor expression. The presence of these defects correlated with autoantibody titers and with disease severity, leading the hypothesis that defects in the secretion of IL-2 and its receptor may result from excessive suppressor activity of either monocytes or T cells. Alternatively, since suppressor T (Ts) cells are also thought to play an accessory role in the suppression of autoreactive B cells, a defect in Ts function might account in part for defective cell-mediated immunity or autoantibody production. No defect was found in Ts cell function from pemphigus vulgaris patients. However, since the Ts cell defect may be antigen specific and not demonstrated by the Con A suppressor assay used in these studies, the results do not conclusively exclude a defect in suppressive activity in pemphigus. Using phenotypic marker studies and a standard blastogenic response assay, it was not possible to demonstrate quantitative or qualitative abnormalities in T cells from patients with pemphigus vulgaris. In vitro assays designed to assess possible immunoregulatory defects that influence IgG synthysis in pemphigus vulgaris have also shown no abnormalities.
In contrast, a marked decrease in the total T lymphocyte count, as well as a depletion of T cells in the paracortical areas of lymph nodes, was demonstrated in patients with fogo selvagem, reflecting a possible defect in cellular immunity. Elevated thymosin alpha, levels, which are known to increase helper T cell numbers and enhance resistance to infectious agents, have been demonstrated in fogo selvagem patients. Levels of thymosin alpha, are usually high in viral infections and low to normal in autoimmune diseases and in nonendemic forms of pemphigus. Hence the elevation of this factor in fogo selvagem patients supports the role of a viral etiology for this disease and distinguishes it immunologically from other variants of pemphigus.
Pathogenic role of Pemphigus Autoantibodies
The clinical observations that support a pathogenic role of pemphigus autoantibodies include
Virtually 100% of patients with pemphigus have IgG autoantibodies bound to the surface of the epidermal cells both in and around lesions as shown by direct IF techniques. Complement proteins are also detected in lesional epidermis, which suggests that complement activation may be implicated in the autoantibody induced epidermal injury in vivo.
In addition, the serum of virtually all patients with active disease contains antiepithelial cell surface autoantibodies, which can be demonstrated by indirect IF procedures using frozen sections of stratified squamous epithelium as tissue substrate. The titer of pemphigus autoantibodies detected in the patient's serum correlates well with the clinical activity and extent of disease. The antigen(s) which these autoantibodies bind is not restricted to human skin alone; these autoantibodies bind to the cell surface of stratified squamous epithelium from all mammal and birds. Pemphigus antigens have been partially characterized from different sources, such as saliva, human epidermis, and epidermal cell cultures. Recent studies by Stanley et al and Jones et al found these antigens to be desmosomalassociated glycoproteins, suggesting that pemphigus autoantibodies may impair the assembly of desmosomes and induce cell detachment. Further studies are needed to clarify this issue.
Plasmaphaeresis has been employed for the treatment of patients with pemphigus. The rationale for this treatment was that removal of circulating autoantibodies with subsequent decrease in their IF titer may lead to clinical improvement of the disease. In fact, with intensive plasmaphaeresis, it is possible to produce both a decrease in circulating autoantibody titers, as well as an improvement of the patient.
Source Unknown
The term pemphigus refers to a group of cutaneous diseases that are characterized by the development of intraepidermal blisters and sometimes mucosal erosions. These diseases are pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, endemic pemphigus foliaceus or fogo selvagem, and pemphigus erythematosus. All forms of pemphigus are characterized by epidermal cell-to-cell detachment (acantholysis), which leads to vesicle (intraepidermal) formation, and the presence of IgG autoantibodies directed against antigenic determinants present on the cell surfaces of differentiating keratinocytes.
Both forms of pemphigus foliaceus are easily differentiated from pemphigus vulgaris and its variants, such as pemphigus vegetans. In pemphigus vulgaris the lesions usually first appear on mucosal surfaces, acantholysis is suprabasilar rather than subcorneal, and the patient's autoantibodies recognize a different epidermal glycoprotein. The salient features of these disorders are summarized as follows
| Differential Features | Pemphigus Vulgaris | Fogo Selvagem | Pemphigus Foliaceus |
| Distribution | Sporadic | Endemic, Brazil | Sporadic |
| Etiology | Unknown | Environmental(?) | Unknown |
| Age | Adults | Children & young adults | Elderly |
| Familial Cases | Rare | Frequent | None |
| Skin Lesions | Deeper, Suprabasilar | Superficial, subcorneal | Superficial, subcorneal |
| Mucosal Lesions | Common | Rare | Rare |
| Passive Transfer | Suprabasilar disease in mice | Subcorneal disease in mice | ? |
| Antigens | 135-kD glypoprotein | Desmoglein I | Desmoglein I |
| Pregnancy | Neonatal Pemphigus | Normal newborns | Normal newborns |
| Prognosis | Guarded | Variable | Variable |
The precise etiology of all forms of pemphigus and the mechanisms that initiate the antibody formation are essentially unknown; however, in certain cases, an etiological agent is suspected. In endemic pemphigus foliaceus, for example, there is strong epidemiological evidence suggesting that an environmental agent is responsible for initiating autoimmunity. Other reports also showed that penicillamine, rifampicin, and captopril are capable of producing a pemphigus like disease.
There also appear to be genetic factors that predispose individuals to developing DRw4 phenotype. Possible genetic associations are discussed in the following text.
Pemphigus has rarely been associated with other autoimmune disorders, such as lupus erythematosus (Senear-Usher syndrome), rheumatoid arthritis, myasthenia gravis, pernicious anemia, Hashimoto's thyroiditis, and tumors, such as benign thymomas. Usually the course of pemphigus is not affected by the presence of autoimmune disorders. Pemphigus has also been associated with various malignancies. Pemphigus is associated with unique autoantibody responses against desmosomal and hemidesmosomal polypeptides in a small percentage of patients who have a paraneoplastic syndrome.
This chapter focuses on the two major diseases of the pemphigus group, pemphigus vulgaris and pemphigus foliaceus, and their clinical variants. The endemic form, fogo selvagem, is stressed, since the clinical presentations of both endemic and nonendemic forms of pemphigus foliaceus are identical, whereas the epidemiological features of fogo selvagem are unique.
Pemphigus Vulgaris and Pemphigus Vegetans
Clinical Presentation
Pemphigus vulgaris is considered the most severe form of pemphigus. Although it may occur at any age, its most common onset is in the fourth, fifth, and sixth decades. It is characterized by the presence of flaccid, exceedingly fragile, noninflammatory bullae that usually arise on normal-appearing skin. These bullae have a tendency to coalesce and rupture easily, resulting in large denuded weeping areas that are the predominant clinical feature. Shearing pressure applied to the skin produces denuding (Nikolsky's sign). Pemphigus vulgaris involves both the skin and the mucous membranes, and in general the initial lesion affects the oral mucosa. Many patients with oral ulcerations are misdiagnosed as having aphthous stomatitis. Typically, after a period of weeks to several months and occasionally up to a year or more, the lesions extend to the head and neck and become generalized. The mucous membrane lesions may involve the conjunctiva, nasal mucosa, and vagina. At times the oral lesions may extend from the vermilion border of the lips to the cardia of the stomach. The larynx may be involved, producing hoarseness and even aphonia. On unusual occasions, the initial lesion may be an unrecognized pyoderma of the scalp in an older patient.
Before the introduction of corticosteroids in the 1950s, pemphigus vulgaris was considered almost uniformly fatal mostly because of protein, fluid, and electrolyte losses or uncontrollable sepsis.
Pemphigus vegetans is a rare form of pemphigus vulgaris. Patients are generally younger than those afflicted with pemphigus vulgaris. This variant can be further divided into Neumann and Hallopeau subtypes. Lesions of the Neumann subtype are initially identical to those of pemphigus vulgaris. However, ulcerations eventual heal, evolving into vegetating lesions localized predominantly in the flexural and intertriginous areas. Pustular lesions are noted especially at the periphery of vegetating lesions. Although the outcome of pemphigus vegetans of Neumann can be similar to pemphigus vulgaris, the former usually pursues a more benign, protracted course.
Before the use of corticosteroids, spontaneous and complete remissions occasionally occurred in patients. Pemphigus vegetans of Hallopeau presents with pustules that develop into vegetating plaques. Bullae are relatively rare. This form of pemphigus pursues a chronic benign course in which complete remissions are not infrequent. Although some authors view pemphigus vulgaris and vegetans as a spectrum, demonstrating differing degrees of host resistance, the concept of "resistance" as applied to pemphigus has not been adequately defined. These variants are probably more historically interesting than clinically valuable.
| Clinical | Flaccid bullae arise on non inflamed skin; oral and mucous membrane involvement; Nikolsky's sign |
| Histopathology | Intraepidermal blister formation; acantholytic process; epidermal basal cells producing "row of tombstones" |
| Direct IF | IgG deposition in epidermal intercellular spaces; IgG4 subclass is dominant response |
| Indirect IF | Approximately 90% of patients possess IgG antibodies against epidermal intercellular space antigen(s) |
| EM studies | Initial event is dissolution of the epidermal intercellular spaces between desmosomes, then separation at the desmo junction |
| Immuno-EM studies | Binding of IgG antibody to antigen(s) in the intercellular substance |
| Immunoblot studies | Technically difficult, but sdme investigators have demonstrated binding of IgG antibody to 130 kD glycoprotein |
| Immunoprecipitation studies | Pemphigus vulgaris antibodies bind pemphigus vulgaris complex composed of a 130 kD glycoprotein and 85 kD glycoprotein (plakoglobin) |
| Passive transfer studies | IgG and F(ab'), fragments of pemphigus antibody induce a tholytic disease in neonatal mice |
| Immunogenetic studies | Increascd frequency of HLA-DRw4 in Ashkenazi Jews and HLA-DRw4 and DRw6 in non-Ashkenazi Jews |
| Treatment | Traditional treatment is high doses of corticosteroids with or without immunosuppressives (i.e., cyclophosphamide); recent studies have employed plasmaphaeresis |
| Prognosis | Before steroid use, 50% mortality within first year of disease, now greater than 95% survival 10 years into the disease |
Source Unknown
Summary At present, initial high-dose prednisone is the treatment of choice for, patients with pemphigus and bullous pemphigoid. To reduce the risk associated with long-term corticosteroid treatment, other immuno suppressants are often given as steroid-sparing agents, Occasionally, the dose of steroids cannot be reduced. In this study, we report six patients with pemphigus vulgaris, pemphigus foliaceous and bullous pemphigoid, in whom the daily corticosteroid dose could only be tapered to acceptable, effective, maintenance levels following treatment with high-dose intravenous gamma globulin.
Pemphigus vulgaris, pemphigus foliaceous and bullous pemphigoid are autoimmune-mediated blistering dermatoses. high-dose corticosteroid therapy usually is used to suppress blistering, although intramuscular gold treatment, dapsone and tetracycline' are also effective, Hi dose steroid therapy is associated with a risk of side effects in the long-term, and plasma exchange, or concomitant therapy with immuno suppressive agents such as azathioprine, cyclophosphamide or cyclosporin are used in an attempt to reduce steroid intake. Recently, high-dose intravenous gamma globulin has been shown to have a steroid-sparing effect in the treatment of pemphigus. We report our experience with this therapy in three patients with pemphigus vulgaris, one patient with pemphigus foliaceous and two patients suffering from bullous pemphigoid.
Although new blister formation was prevented, the eroded surfaces did not heal even when the prednisone dosage was increased to 120mg/day, and maintained at this level for 10 days. Following intravenous administration of gamma globulin (0-4 g/kg per day) for 5 consecutive days, the eroded areas started to heal, and the daily prednisone dose was tapered to 40 mg over a period of 5 weeks, and subsequently to 10 mg daily within 14 weeks (Fig, 1), At present, 10-15mg of prednisone daily is sufficient to suppress blistering.
She was therefore given intravenous gamma globulin (0-4g/kg per day) for 5 consecutive days. This produced healing of pre-existing lesions, and prevented further blistering. The prednisone was reduced gradually to 20 mg/day within 17 weeks (Fig. 1). After discharge from hospital, no further blisters occurred during 80 days of follow-up.
After treatment with intravenous gamma globulin (0-4g/kg per day) for 5 consecutive days, his skin improved, and the blistering stopped (Fig. 2). His dose of prednisone was reduced to 12 t 5 mg/day within 2 1 weeks (Fig. 3). and to 1 0 mg in the next 1 3 weeks, No further blisters have appeared to date,
In addition to dexamethasone (Os 5 mg/day) and azathioprine (50 mg/day) the patient was treated with intravenous gamma globuhn (0-4 g/kg per day) for 5 consecutive days. Despite this treatment, new blisters continued to develop. Plasma exchange and pr@one (80mg/day) with azathioprine (150 mg/ day) were also Ineffective, After pulse therapy with intravenous prednisone (1000mg/day for 3 consecutive days), an oral dose of 60 mg, and then 4 5 mg/day, with azathioprine 1 50 mg/day, was required to obtain remission. The prednisone dose could not be reduced further, and he was therefore given a second course of intravenous gamma globulin (0,4g/kg per day) for 5 consecutive days. Thereafter, the prednisone dosage was gradually reduced to 20mg/day within 11 weeks (Fig. 4). This was sufficient to prevent relapse during a follow-up period of 77 days.
To reduce the risks of long-term, high-dose steroid therapy the dose is tapered to an acceptable, effective maintenance level as soon as possible, and may be facilitated by combining steroids with plasma exchange, intramuscular gold, or another immuno suppressive agent, such as azathioprine, cyclophosphamide or cyclosporin
However, despite adjuvant treatment, dependence on high steroid doses may persist. High-dose intravenous gamma globulin is useful in the treatment of antibody-mediated diseases, such as idiopathic thrombocytopenic purpura. and autoimmune neutropenia. Godard et al.''reported a temporary improvement of bullous pemphigoid in eight of 11 patients treated with intravenous gamma globulin. Failure of high-dose intravenous gamma globulin treatment has been reported in three patients with pemphigus vulgaris and in two patients with bullous pemphigoid. In both studies, nearly all patients were treated with high-dose intravenous gamma globulin as a single agent-hence, its steroid-sparing effect can not be assessed.
Humbert et al. reported a significant improvement of the disease, and a steroid-sparing effect of high dose intravenous gamma globulin, in a patient with pemphigus.
We have treated six patients with pemphigus and bullous pemphigoid using adjuvant intravenous gamma globulin. In each patient. and especially in those with pemphigus, blistering was suppressed, and the treatment enabled reduction of the dose of prednisone to acceptable levels.
High-dose intravenous gamma globulin is thought to interact with several immune-mediated mechanisms, anti-idiotypic antibodies in the gamma globulin preparation can exhibit specific antigen-binding properties, and may neutralize circulating antibodies by forming dimers. In this way, anti-idiotypic antibodies prevent autoantibodies binding to the surface of epidermal skin or to the basement membrane. In addition, the removal of autoantibodies (as dimers) by cells of the reticuloendotheual system is facilitated. Monomeric and dirneric IgG block Pc-raceptors on cytotoxic effector calls responsible for antibody-dependent ceu-mediated cytotoxicity, and In vitro and in vivo studies have shown that the synthesis of antibodies is reduced, due to the binding and down-regulation of specific B-cell receptors.
The finding that the titre of circulating autoantibodies was reduced in our patient with pemphigus foliaceous (case 4) supports these observations. High-dose intravenous gamma globulin therapy is not associated with serious side-effects. Symptoms including dyspnea, abdominal pain, headache. hyperhidrosis and tachycardia may occur occasionally. and generally resolve when the infusion speed is reduced. Anaphylactic reactions are rare if patients with IgA deficiency are excluded. Some gamma globulin preparations have transmitted hepatitis C virus, but generally the preparations are safe.
When adjuvant immuno suppression fails to provide a steroid-sparing effect, high-dose intravenous gamma globulin offers an alternative. This treatment is expensive, and should be reserved for patients with severe disease who require high doses of steroid, until cost-benefit studies have been performed.
(Br J Dermatol 1995;133:83-87)(Abstract) by O. Mourellou
v274 JAMA, The Journal of the American Medical Association Oct 18 '95
p1178P(1) COPYRIGHT 1995 American Medical Association
We present a retrospective analysis of 48 patients with pemphigus vulgaris (PV) who were seen between 1978 and 1988. They were divided into three treatment groups: 25 (group A) received 40-100 mg of oral prednisone daily; eight (group B) received >100 mg of prednisone daily; 15 (group C) received 40 mg of oral prednisone every other day and azathioprine 100 mg daily. A second immuno suppressive agent was subsequently added to the treatment regimen of three patients in group A and eight patients in group B.
By 1989, 10% of the patients had been able to discontinue all therapy, and were in complete remission. Sixty-five per cent of patients were on maintenance therapy, but in clinical remission. Twenty-five per cent of the patients had died (eight in group A [31%] and four in group B [50%]) either as a consequence of the disease or its treatment. None of the patients in group C had died. Most of the deaths occurred during the first 2-3 months of therapy. Morbidity and mortality were related to the severity of the disease, to the maximum dose of prednisone required to induce remission, and to the presence of other diseases. Patients needing a total of 5 g or more of prednisone to induce a remission during the acute stage had a high mortality rate.
Pemphigus Vulgaris
This autoimmune disorder, which generally appears in middle age, affects skin and mucous membranes and is characterized by bullae of various sizes. The oral cavity is almost invariably involved in pemphigus vulgaris, and these lesions are often the first manifestation. Oral bullae are transient; the usual picture consists of multiple nonspecific erosions, mainly on the soft palate and buccal mucosa, with fragments of surface epithelium at the borders. Occasionally, a desquamative gingivitis is seen, and the oropharynx, hypopharynx, and larynx may be involved. Pain is the dominant symptom.
Widespread skin ulcerations pemphigus vulgaris can lead to systemic sepsis and death. In a 20-year study of 107 patients who were treated with corticosteroids, Rosenberg and colleagues found a 32% mortality rate. High-dose corticosteroid therapy was a major cause of morbidity and mortality. This led to the use of adjunctive agents to reduce the corticosteroid dosage necessary for remission. An association with pemphigus vulgaris and thymic neoplasms has been established. Microscopic examination of tissue removed from the lesion's margin shows clefting of the epithelium above the stratum gemiinativum and acantholytic (Tzanck) cells within the fluid-filled space that develops. A variable degree of inflammatory infiltration develops in the submucosa.
Nevertheless, epithelial loss and inflammatory infiltration fall to yield a definitive diagnosis. This is best done by direct immunofluorescence. Demonstration of IgG, IgA, and IgM immune complexes in the intraepithehal layer confirms the diagnosis and differentiates pemphigus vulgaris from the other bullous disorders.
When indirect immunofluorescence is used during the active stage, the serum is positive for immune complexes in 95% of the cases. In remission, the titer is lower or even normal. Consequently, indirect immunofluorescence may be used to monitor the effectiveness of drug therapy.
Prescribe high-dose corticosteroids (60 to 180 mg/d) to induce remission. This dosage can be reduced with use of an adjunctive agent, such as dapsone, cyclophosphamide, methotrexate, or azathioprine.
Bullous Pemphigoid
Although this autoimmune condition resembles pemphigus vulgaris, it has different features. These include a decreased incidence of oral lesions; their development after, rather than before, that of skin lesions; the nature of the oral lesions; and the histologic picture. The mean age of incidence is in the sixth and seventh decades. Although the majority of lesions consist of bullae, there may also be vesicles. The oral lesion distribution is similar to that in pemphigus vulgaris. In an analysis of 25 cases, Laskaris and coworkers reported involvement of buccal mucosa, 52%; soft palate, 40%; tongue, 24%; lower lip, 20%; gingiva, 16%; upper lip, 8%; and floor of mouth, 8%. The intense, widespread, desquamative gingivitis in bullous pemphigoid is of diagnostic importance.
Histologic examination shows subepithehal bullae with cleavage at the epithehal-connective tissue junction. The epithelium is normal. Acantholysis is absent, and the submucosa shows an intense inflammatory reaction. The diagnosis is confirmed when direct immunofluorescence reveals immune complexes binding IgG and C3 in the epidermal basement membrane.
Treat these patients with systemic corticosteroids, 40 to 80 mg/d. As with pemphigus vulgaris, azathioprine, cyclophosphamide, dapsone, or methotrexate can be used adjunctively.[3]
Mucous Membrane Pemphigoid
The conjunctiva and oral cavity are the primary sites of involvement here, but mucosal lesions have been reported in the nose, pharynx, esophagus, larynx, urogenital tract, and anus, as well as the skin. The incidence of ocular involvement ranges from 10% to 62% in different studies.
Mucous membrane pemphigoid lesions are vesiculo bullous and often heal with scarring (hence the term cicatricial pemphigoid), except in the oral cavity. Adhesions commonly occur in the eye (symblepharons). The mean age of occurrence is 60, and women are affected two to three times as often as men. The disease generally is chronic, but protracted intervals of remission may occur.
In a series of 85 cases reviewed by Sklar and McCarthy, regional involvement included the oral cavity, 100%; conjunctiva, 59%; genitalia, 20%; skin, 9%; nose, 8%; rectum, 5%; urethra, 5%; and esophagus, 3%. In their series of 65 cases, Silverman and fellow investigators' reported that the most common sites of oral involvement were the gingiva, 94%; palate, 32%; buccal mucosa, 29%; floor of mouth, 5%; and tongue, 5%.
In my practice, I have also seen lesions in the oropharynx and larynx; these were generally in conjunction with oral cavity involvement. The oral cavity lesions of mucous membrane pemphigoid are generally smaller than those of pemphigoid vulgaris and bullous pemphigoid, and they develop more slowly. Similar to the lesions of bullous pemphigoid, they are often accompanied by an intense erythematous and desquamative gingivitis (Figure 3). The histologic picture is also one of subepithelial clefting of the mucosa, without acantholysis and with an intense inflammatory infiltrate. Direct immunofluorescence demonstrates the deposition of immune complexes IgG and C3 in the basement membrane. Although tissue studies may not differentiate mucous membrane pemphigoid from bullous pemphigoid, the clinical picture is helpful. The intense oral and ocular involvement and scarcity of skin lesions found in mucous membrane pemphigoid differs from the extensive skin involvement and infrequent oral lesions seen with bullous pemphigoid. For local pain control, prescribe an emollient mouthwash (eg, diphenhydramine syrup). Use systemic prednisone as well, but the required dosage (20 to 40 mg/d) is lower than that needed for pemphigus vulgaris.
End
Pemphigus in remission: value of negative direct immunofluorescence in management.
(J Am Acad Dermatol 1994;30:547-550) (Abstract) by K.V. Ratnam and Bryan K. Pang v271 JAMA, The Journal of the American Medical Association June 8 '94 p1722D(1)
COPYRIGHT 1994 American Medical Association
Background: Pemphigus vulgaris is characterized by relapses and remission, and there are currently no sensitive markers to predict remission.
Objective: Our purpose was to determine if direct immunofluorescence (DIF) performed during clinical remission of pemphigus is useful in management of the disease.
Methods: Twenty-eight patients with pemphigus that was in clinical remission (i.e., patients who were taking low-dose prednisolone [10 mg/day] and had been blister-free for at least 6 months) underwent DIF. Therapy was then discontinued and patients were prospectively followed up for 5 years.
Results: Twenty-two patients had negative results and six patients had positive results of DIF. The disease remained in remission in three quarters of the patients with negative results of DIF. Of those who had a relapse, intercellular C3 on DIF and oral lesions on initial presentation were important risk factors, and the relapses in patients with negative results of DIF were mild. The biopsy site was unimportant. All patients with positive results of DIF had major relapses within 3 months of cessation of therapy.
Conclusion: DIF should be performed before therapy is discontinued. A negative DIF finding is a good indicator of remission in pemphigus. (1994;30:547-550) K. V. Ratnam and Bryan K. Pang, National Skin Centre, 1 Mandalay Rd, Singapore 1130.
Summary
We report the successful treatment of a 36-year-old man with recalcitrant pemphigus with pulsed intravenous immunoglobulin therapy, dexamethasone and cyclophosphamide.
Case report
A 36-year-old man presented to the (otorhinolaryngology) department in March 1990 with a 3-month history of mouth blisters and ulceration, nasal crusting and sore eyes. Following unsuccessful treatment with chloramphenicol and sodium cromoglycate eye drops, a biopsy of the oral mucosa was taken. This showed ulceration with a single layer of intact basal cells (the 'tombstone effect') together with suprabasal acantholysis of squamous cells, and was highly suggestive of pemphigus vulgaris. Although no specimen for direct immunofluorescence had been taken, a diagnosis of pemphigus vulgaris was made and the patient was admitted to the dermatology ward and commenced on oral prednisolone, 120mg daily.
Subsequent direct and indirect immunofluorescence confirmed the diagnosis. Oral azathioprine, 50 mg daily, was commenced 1 week after admission and increased to 150 mg daily over the next 2 weeks. Effective control of his disease was maintained with prednisolone, 10- 20 mg daily, and azathioprine, 150-200 mg daily, until June 1991. when further severe blistering of the mouth failed to respond to high-dose oral corticosteroids (prednisolone 60 mg daily). Intramuscular methotrexate, 5 mg/week, was introduced in July 1991 and increased by 5 mg/week to a maximum of 25 mg/week. The condition improved but a liver biopsy showed severe (grade 2) coarse granular haemosiderin deposition with preservation of the normal hepatic architecture, consistent with haemochromatosis. The diagnosis of idiopathic familial haemochromatosis was confirmed by a highly elevated serum ferritin (839~Lg/l; normal range 16-330 ~g/l) in the absence of blood transfusion and alcohol abuse. The methotrexate was stopped and, from that time, regular venesection was performed to keep the ferritin within normal limits.
New mouth blisters developed, which were poorly controlled by minocycline 50 mg b.d., together with an increase in the dose of prednisolone. Dapsone, 100 mg daily, commenced in March 1992, and cyclophosphamide, 50 mg b.d., commenced in June 1992 and increased to 100 mg b.d. in luly 1992, similarly had little effect. Cyclosporin A (CyA), 3 mg/kg per day, was started in October 1992 after a normal isotopic glomerular filtration rate (GFR) had been confirmed. The dose of CyA was increased to a maintenance dose of 5 mg/kg per day without improvement. In January 1993, pulsed intravenous cyclophosphamide (500 mg by slow intravenous infusion, followed by 50 mg daily by mouth) and dexamethasone (100 mg/day for 3 days) were given. The oral lesions resolved but recurred after 1 month. Three further monthly pulses of dexamethasone and cyclophosphamide were given, together with oral cyclophosphamide, 50 mg/day. but the initial benefit was not sustained. Twice-weekly plasmapheresis was commenced in May 1993, together with pulsed dexamethasone and cyclophosphamide. There was little response and, in November 1993, monthly pulses of intravenous gammaglobulin (39 gandoglobulin daily for 5 days initially, and for 3 days subsequently) was commenced together with continuation of the monthly pulsed dexamethasone and cyclophosphamide. There was a marked clinical improvement with resolution of the orofacial erosions, which has remained to date. In addition, the previously persistently elevated indirect immunofluorescent pemphigus antibodies (1/1280- 1/320) reduced to an undetectable level by March 1994. With the exception of a very low titre of indirect immunofluorescent antibodies in January 1995, the antibodies have remained undetectable to date (Fig. 1). We were able to stop the oral cyclophosphamide in December 1994, and the intravenous cyclophosphamide in February 1995, without clinical deterioration. The current treatment is with monthly pulses of dexamethasone 100 mg and Sandoglobulin, 39g daily for 3 days. We plan to stop the pulsed dexamethasone in near future.
Discussion
Pemphigus vulgaris is a potentially life-threatening autoimmune blistering disorder that has multiple clinical variants and is often difficult to control. The aetiology is not fully understood, but it is known that patients with pemphigus vulgaris develop autoantibodies to 85kDa, 130)kDa and 210)kDa antigens. Treatment often involves the use of; immunosuppressive agents and steroids have been the mainstay of clinical management. Other well-tried immunosuppressive drugs include azathioprine, dapsone, sodium aurothiomalate, chlorambucil, methotrexate and cyclophosphamide. Newer therapies include CyA4 and prostaglandin E2. Treatments aimed at removing autoantibodies (plasmapheresis)h or modifying peripheral blood leucocytes (extracorporeal photophoresis), have also been used, with some success. Plasmapheresis is usually used in combination with immunosuppressive drugs as rebound autoantibody production often follows the plasmapheresis.
Intravenous immunoglobulin therapy (IVIT) has a broad ran~e of clinical applications including primary and secondary immunodeficiency, haematological, and autoimmune disorders. Initial in vitro work seemed to indicate that IVIT did not prevent acantholysis of skin organ cultures. Clinical corroboration was added when three patients failed to respond to IVlT, albeit without the concomitant use or immunosuppressives and after just one dose. Successful treatment of a patient with pemphigus with continuing monthly IVIT with steroids and azathioprine, was subsequently reported. It seems likely that, as with plasmapheresis, the action of IVIT is at least assisted by adjunct immunosuppression.
The mechanism of action of IVIT is largely unknown. Reports indicate competitive interaction with endogenous antibodies, an enhanced negative feedback on endogenous autoantibody production, interference with immune complex interactions, modification of complement-mediated immune damage to cells, 12 or a combination of these processes.
Acknowledgment
We are grateful to Dr F.Wojnarowska, Oxford, U.K., for advice, and to Dr J.Theaker, Southampton, U.K., for histological advice.